{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:10:36Z","timestamp":1760123436112,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"MEXT\/JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP21H03024"],"award-info":[{"award-number":["JP21H03024"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nakatomi Foundation","award":["JP21H03024"],"award-info":[{"award-number":["JP21H03024"]}]},{"name":"Takeda Science Foundation","award":["JP21H03024"],"award-info":[{"award-number":["JP21H03024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective \u03b22-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL\/6J mice. Neither a selective \u03b11-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, \u03b22-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral \u03b22-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development.<\/jats:p>","DOI":"10.3390\/ijms24043465","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T02:55:54Z","timestamp":1675911354000},"page":"3465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Peripheral Beta-2 Adrenergic Receptors Mediate the Sympathetic Efferent Activation from Central Nervous System to Splenocytes in a Mouse Model of Fibromyalgia"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6875-371X","authenticated-orcid":false,"given":"Shiori","family":"Yamashita","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Dozono","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6638-1916","authenticated-orcid":false,"given":"Shota","family":"Tobori","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7438-732X","authenticated-orcid":false,"given":"Kazuki","family":"Nagayasu","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuji","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-0978","authenticated-orcid":false,"given":"Hisashi","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki 852-8521, Japan"},{"name":"Graduate Institute of Pharmacology, National Defense Medical Center, Nei-hu, Taipei 114201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Siracusa, R., Paola, R.D., Cuzzocrea, S., and Impellizzeri, D. (2021). Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083891"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15022","DOI":"10.1038\/nrdp.2015.22","article-title":"Fibromyalgia","volume":"1","author":"Ablin","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jpain.2009.06.012","article-title":"Central sensitization: A generator of pain hypersensitivity by central neural plasticity","volume":"10","author":"Latremoliere","year":"2009","journal-title":"J. Pain"},{"key":"ref_4","first-page":"364","article-title":"Functional imaging of pain in patients with primary fibromyalgia","volume":"31","author":"Cook","year":"2004","journal-title":"J. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/ALN.0000000000002130","article-title":"Neuroinflammation and Central Sensitization in Chronic and Widespread Pain","volume":"129","author":"Ji","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbi.2018.09.018","article-title":"Brain glial activation in fibromyalgia\u2014A multi-site positron emission tomography investigation","volume":"75","author":"Albrecht","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/ana.24065","article-title":"Hyperexcitable C nociceptors in fibromyalgia","volume":"75","author":"Serra","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/j.jfma.2021.02.003","article-title":"Altered sensory nerve excitability in fibromyalgia","volume":"120","author":"Teng","year":"2021","journal-title":"J. Formos Med. Assoc."},{"key":"ref_9","first-page":"77","article-title":"Fibromyalgia and autoimmune diseases: The pain behind autoimmunity","volume":"10","author":"Buskila","year":"2008","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1159\/000341664","article-title":"Inflammatory\/stress feedback dysregulation in women with fibromyalgia","volume":"19","author":"Bote","year":"2012","journal-title":"Neuroimmunomodulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1111\/j.1526-4637.2011.01179.x","article-title":"MCP-1 and IL-8 as pain biomarkers in fibromyalgia: A pilot study","volume":"12","author":"Ang","year":"2011","journal-title":"Pain Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.55563\/clinexprheumatol\/iitbcp","article-title":"Bioinformatics analysis of gene and microRNA targets for fibromyalgia","volume":"39","author":"Qiu","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.3390\/jcm9061814","article-title":"Gene Expression Profiling in Fibromyalgia Indicates an Autoimmune Origin of the Disease and Opens New Avenues for Targeted Therapy","volume":"9","author":"Dolcino","year":"2020","journal-title":"J. Clin. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/1097-4598(200101)24:1<37::AID-MUS4>3.0.CO;2-8","article-title":"Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia","volume":"24","author":"Sluka","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1523\/JNEUROSCI.18-08-03043.1998","article-title":"Vagotomy-induced enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated","volume":"18","author":"Khasar","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pain.2005.03.040","article-title":"Repeated sound stress enhances inflammatory pain in the rat","volume":"116","author":"Khasar","year":"2005","journal-title":"Pain"},{"key":"ref_17","first-page":"52","article-title":"Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia","volume":"64","author":"Nishiyori","year":"2008","journal-title":"Mol. Pain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ynpai.2017.04.002","article-title":"LPA1 receptor involvement in fibromyalgia-like pain induced by intermittent psychological stress, empathy","volume":"1","author":"Ueda","year":"2017","journal-title":"Neurobiol. Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.pain.2009.05.024","article-title":"Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: A putative animal model of fibromyalgia","volume":"146","author":"Nagakura","year":"2009","journal-title":"Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"600166","DOI":"10.3389\/fnins.2020.600166","article-title":"Allodynia by Splenocytes From Mice With Acid-Induced Fibromyalgia-Like Generalized Pain and Its Sexual Dimorphic Regulation by Brain Microglia","volume":"14","author":"Ueda","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.jpain.2006.11.007","article-title":"Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats","volume":"8","author":"Yokoyama","year":"2007","journal-title":"J. Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e525","DOI":"10.1038\/cddis.2013.54","article-title":"Minocycline selectively inhibits M1 polarization of microglia","volume":"4","author":"Kobayashi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0889-1591(89)90029-9","article-title":"Origin of noradrenergic innervation of the spleen in rats","volume":"3","author":"Bellinger","year":"1989","journal-title":"Brain Behav. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0361-9230(81)80072-X","article-title":"Sympathetic innervation of murine thymus and spleen: Evidence for a functional link between the nervous and immune systems","volume":"6","author":"Williams","year":"1981","journal-title":"Brain Res. Bull."},{"key":"ref_25","first-page":"373","article-title":"The actions of drugs on the smooth muscle of the capsule and blood vessels of the spleen","volume":"25","author":"Davies","year":"1973","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev.pa.35.040195.002221","article-title":"Catecholamine influences and sympathetic neural modulation of immune responsiveness","volume":"35","author":"Madden","year":"1995","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_27","first-page":"595","article-title":"The sympathetic nerve--an integrative interface between two supersystems: The brain and the immune system","volume":"52","author":"Elenkov","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5291","DOI":"10.2741\/3598","article-title":"Neurobiology of depression, fibromyalgia and neuropathic pain","volume":"14","author":"Maletic","year":"2009","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0014-2999(94)90742-0","article-title":"Identification of beta-adrenoceptors in rat lymph nodes and spleen: An autoradiographic study","volume":"262","author":"Revilla","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","first-page":"487","article-title":"Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo","volume":"53","author":"Kohm","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11307-005-0951-x","article-title":"Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain","volume":"7","author":"Elsinga","year":"2005","journal-title":"Mol. Imaging Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1152\/jn.1999.81.3.1104","article-title":"Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors","volume":"81","author":"Khasar","year":"1999","journal-title":"J. Neurophysiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.autneu.2014.01.006","article-title":"Autonomic regulation of cellular immune function","volume":"182","author":"Bellinger","year":"2014","journal-title":"Auton. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11008","DOI":"10.1073\/pnas.0803237105","article-title":"Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia","volume":"105","author":"Ochani","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5781","DOI":"10.1113\/JP271539","article-title":"Anti-inflammatory properties of the vagus nerve: Potential therapeutic implications of vagus nerve stimulation","volume":"594","author":"Bonaz","year":"2016","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.3390\/ijms16035635","article-title":"Molecular mechanisms underlying \u03b2-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells","volume":"16","author":"Lorton","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","first-page":"241","article-title":"Differential cotransmission in sympathetic nerves: Role of frequency of stimulation and prejunctional autoreceptors","volume":"290","author":"Todorov","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","first-page":"1275","article-title":"T helper 1 response is correlated with widespread pain, fatigue, sleeping disorders and the quality of life in patients with fibromyalgia and is modulated by hyperbaric oxygen therapy","volume":"38","author":"Guggino","year":"2020","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.autrev.2017.11.010","article-title":"Physical activity and autoimmune diseases: Get moving and manage the disease","volume":"17","author":"Sharif","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.12659\/MSM.906184","article-title":"Norepinephrine Inhibits Th17 Cells via \u03b22-Adrenergic Receptor (\u03b22-AR) Signaling in a Mouse Model of Rheumatoid Arthritis","volume":"24","author":"Liu","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1111\/febs.14166","article-title":"Reciprocal modulation of helper Th1 and Th17 cells by the \u03b22-adrenergic receptor agonist drug terbutaline","volume":"284","author":"East","year":"2017","journal-title":"FEBS J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1523\/JNEUROSCI.5564-10.2011","article-title":"Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice","volume":"31","author":"Cheng","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10360","DOI":"10.1523\/JNEUROSCI.1041-10.2010","article-title":"Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain","volume":"30","author":"Chen","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jpain.2014.01.165","article-title":"Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia","volume":"10","author":"Chen","year":"2014","journal-title":"Mol. Pain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neuint.2016.11.004","article-title":"Stimulation of spinal dorsal horn \u03b22-adrenergic receptor ameliorates neuropathic mechanical hypersensitivity through a reduction of phosphorylation of microglial p38 MAP kinase and astrocytic c-jun N-terminal kinase","volume":"101","author":"Zhang","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"112331","DOI":"10.1016\/j.biopha.2021.112331","article-title":"\u03b22-adrenoreceptor agonist ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of mitochondrial biogenesis","volume":"144","author":"Chen","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.expneurol.2009.10.008","article-title":"Chronic treatment with agonists of beta(2)-adrenergic receptors in neuropathic pain","volume":"221","author":"Yalcin","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.bbi.2010.11.018","article-title":"Adoptive transfer of peripheral immune cells potentiates allodynia in a graded chronic constriction injury model of neuropathic pain","volume":"25","author":"Grace","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMC Vet. Res., 16.","DOI":"10.1186\/s12917-020-02451-y"},{"key":"ref_50","first-page":"894","article-title":"Electroacupuncture reduces chronic fibromyalgia pain through attenuation of transient receptor potential vanilloid 1 signaling pathway in mouse brains","volume":"23","author":"Yen","year":"2020","journal-title":"Iran J. Basic Med. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:28:05Z","timestamp":1760120885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043465"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043465","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}